Molecules conveying the benefits of exercise on brain health revealed

A new study conducted by a group of scientists from Dana-Farber Cancer Institute and Harvard Medical School reports a new, possible pathway linking three molecules that could explain the mechanisms behind the benefits of endurance exercise to brain health. These findings, published in the journal Cell Metabolism, could provide us with alternative treatments for several neurological diseases or dementia.

Juvenal addressed to roman citizens “Mens sana in corpora sano” in Satire X, which is translated as “a healthy mind in a healthy body”. Long before the Romans, Ancient Greeks lived by the same notion. Nowadays and separated from its initial context, it is utilized to promote physical exercise meaning that a healthy body can produce or sustain a healthy mind. While scientists have proved the positive impact of exercise on cognitive function and on serious illnesses’ outcomes such as depression, epilepsy, Alzheimer’s and Parkinson’s disease, the underlying mechanisms and pathways still remain unclear.

Scientists know that one of the important molecular mediators for the brain beneficial responses to exercise is a growth factor called brain-derived neurotrophic factor (BDNF). In both animal models and humans, BDNF is mostly found in the hippocampus area and thus promoting brain cells development and survival. BDNF promotes generation of new nerve cells and nerve connections that optimize learning and memory. On the contrary, BDNF deficit is associated with decreased volume of brain regions, deficits in memory, increased anxiety and depression.

Bruce Spiegelman, professor of cell biology at Harvard Medical School, and his colleagues have found another important exercise-related protein, called FNDC5. FNDC5 is found on the membrane of muscle cells but after endurance training it is secreted in the blood circulation as irisin, a truncated form of FNDC5. Once released, Irisin reaches other body parts, the brain included. Specifically, its expression in the central nervous system led the researchers to investigate its expression and function in the brain.

In the new research led by Spiegelman and Michael E. Greenberg, PhD, chair of neurobiology, mice after one-month endurance exercise showed increased activity of a metabolic regulatory molecule in muscles, named PGC-1α, which led to a rise in the muscle protein FNDC5. This rise in turn boosted the expression of the BDNF protein in the hippocampus, a brain part involved in learning and memory.

After having shown the FNDC5 function as a molecular mediator between exercise and increased BDNF in the brain, the scientists artificially increased FNDC5 in mice, using harmless viruses, to see if even without exercise they would have the same effect. They measured BDNF gene expression in the hippocampus of mice, and they found a significant increase of BDNF these cells, as seen in mice after exercise.

These findings provide a molecular pathway activated in the hippocampus linking PGC-1a, FNDC5 and BDNF and explaining the previously observed effect of BDNF activity’s increase during exercise.

“What is exciting is that a natural substance can be given in the bloodstream that can mimic some of the effects of endurance exercise on the brain,” says Spiegelman.

These findings can be very beneficial, even though the authors acknowledge that further research is required to determine if injecting FNDC5 can actually improve animals’ cognitive function before trying to produce a more stable form of the irisin as a drug. An application to humans and the development of neuroprotective factors into drugs would have an enormous impact on quality of life of aging population and neurological diseases’ prognosis and treatment.